This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated
methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of
hypermethioninemia. The genetic conditions are: (1)
Homocystinuria due to
cystathionine β-synthase (
CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964.
Hypermethioninemia is due chiefly to remethylation of the accumulated
homocysteine. (2) Deficient activity of
methionine adenosyltransferases I and III (MAT I/III), the
isoenzymes the catalytic subunit of which are encoded by MAT1A.
Methionine accumulates because its conversion to
S-adenosylmethionine (
AdoMet) is impaired. (3)
Glycine N-methyltrasferase (
GNMT) deficiency. Disruption of a quantitatively major pathway for
AdoMet disposal leads to
AdoMet accumulation with secondary down-regulation of
methionine flux into
AdoMet. (4)
S-adenosylhomocysteine (AdoHcy)
hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many
AdoMet-dependent
methyltransferases, producing accumulation of
AdoMet and, thereby,
hypermethioninemia. (5)
Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial
aspartate-
glutamate transporter may produce (usually transient)
hypermethioninemia, the immediate cause of which remains uncertain. (6)
Fumarylacetoacetate hydrolase (FAH) deficiency (
tyrosinemia type I) may lead to
hypermethioninemia secondary either to liver damage and/or to accumulation of
fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of
hypermethioninemia accompanied by elevations of plasma
AdoMet include
mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a)
Liver disease, which may cause
hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient
hypermethioninemia. (c) Ingestion of relatively large amounts of
methionine which, even in full-term, normal-
birth-weight babies may cause
hypermethioninemia.